US6864285B1 - Covalent derivatives of alkanolamides of monocarboxylic and dicarboxylic acids functionally active on the CB2 cannabinoid receptor - Google Patents

Covalent derivatives of alkanolamides of monocarboxylic and dicarboxylic acids functionally active on the CB2 cannabinoid receptor Download PDF

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US6864285B1
US6864285B1 US10/030,061 US3006102A US6864285B1 US 6864285 B1 US6864285 B1 US 6864285B1 US 3006102 A US3006102 A US 3006102A US 6864285 B1 US6864285 B1 US 6864285B1
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Cristina Comelli
Francesco Della Valle
Maria Federica Della Valle
Gabriele Marcolongo
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Innovet Italia SRL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/17—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/18—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/12—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/04—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D307/18—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/20—Oxygen atoms

Definitions

  • This application is a 35 U.S.C. ⁇ 371 application.
  • the present invention relates to novel covalent derivatives of alkanolamides of monocarboxylic and dicarboxylic acids with aminoalcohols which can usefully be used as agonists of the CB2 cannabinoid receptor and hence as drugs active in pathological conditions which can be controlled by stimulation and/or costimulation of this receptor.
  • Pharmacological effects of the cannabinoids not on the central nervous system such as, for example, vascular and endo-ocular hypotensive effects and anti-asthmatic and muscle-relaxant effects have been known for some time but, because of the concomitant psychomimetic effects of these molecules, their therapeutic use is limited to the treatment of very serious pathological conditions such as the cachetic states associated with AIDS and, in any case, in particularly controlled clinical situations (Hollister L. E. Pharmacol. Rev. 1986, 38: 1-20). With regard to the multiplicity of the effects of the cannabinoids, the cell and molecular mechanisms upon which these are based are currently under active investigation.
  • CB cannabinoid receptors have been studied in particular.
  • SNC central nervous system
  • CB2 receptor which is located mainly in peripheral cells of the immune system and has recently been found in the T-lymphocytes
  • the CB2 receptors can mediate the effects of the cannabinoids on cells of the immune system such as the mast cells and the lymphoctyes, by inhibitory modulation of the levels of pro-inflammatory cytokines which are expressed and secreted in excess by these cells when they are hyperactivated by exposure to tissue toxae of various kinds (Matsuda L. A. Cit. Rev. Neurobiol. 1997, 11: 143-146). It is therefore considered that functional agonists of the CB2 receptor—together with functional agonists of the CB1 receptor which have recently also been found at the level of the peripheral nervous system (Hohmann A. G. et al. 1997 Abstract Soc. Neurosci. 23: 1954; Richardson J. D.
  • the neurokine NGF is a fundamental modulator of the neuro-immuno-inflammatory processes triggered by noxae of various kinds, many of the cell populations being involved in these NGF-dependent processes for their survival, maturation, differentiation and gene expression (Levi-Montalcini R. et al. TINS 1996, 19: 514-520).
  • the receptor known as trk—which has a high affinity for NGF, is expressed at the level of the peripheral nervous system, of the tissue macrophages, and of various cell lines with an immune character such as mast cells, basophilic cells and lymphoctyes.
  • these tissue populations also express the cannabinoid receptors CB1 and CB2, although with a different quantitative pattern (Galiegue S. et al. Eur. J. Pharmacol. 1995, 232: 54-61).
  • NGF has recently been shown to facilitate and strengthen gene expression and replication of the HIV virus (Ensoli F. et al. 1994 (Virology, 200: 668-676).
  • the levels of NGF neurokine in the serum of patients suffering from AIDS are particularly high and play a part in the progress of the disease (Pica F. et al. AIDS 1998, 12: 2025-2029). It has recently been shown that, in conditions of antigenic stimulation, high levels of NGF strengthen the return, proliferation and tissue differentiation of the circulating monocytes to macrophages.
  • macrophages by means of suitable chemoreceptors, are tissue reservoirs of the virus and elements of increased tropism for the T-lymphocytes at the sites of inflammation where the propagation of HIV is greatly facilitated (Di Marzio P. et al. AIDS Res. H. Retrov. 1998, 14: 129-138; Gurwitz D. et al. Mol. Med. Today 1998, 4: 196-200).
  • endocannabinoids functionally active at the CB1 and CB2 receptors modulate differentially the expression and/or the secretion of proinflammatory cytokine such as, of example, IL4, by the monocytes/macrophages (Berdishev E. V. et al. Eur. J. Pharmacol. 1997, 330: 231-240). It is also known that, not only the serum levels, but also the tissue levels of NGF are particularly high during neuro-immuno-inflammatory processes (Levi-Montalcini R. TINS 1996, 19: 514-520).
  • the mast cell is the seat of synthesis, storage and release of biologically active NGF which is readily released by the mast cell in response to neurogenic and immunogenic stimuli (Leon A. et al. Proc. Natl. Acad. Sci. U.S.A., 91: 3739-3743). Both the antigenic stimulus represented by the viral protein gp120, and also the neurogenic stimulus represented by the substance P which is released at endothelial level in conditions of exposure to the HIV virus (Annunziata P. et al AIDS 1998, 12: 2377-2385) are activators of mast cell hyper-degranulation.
  • N-acylvanillin amide molecules which are functional agonists of the CB1 receptor, given their chemical construction, also bring about a functional occupation of the vanilloid receptor VR which results in a significant strengthening of the NGF desensitizing effect brought about by the functional activation of the CB1 receptor by means of N-acylvanillin amide (Di Marzo et al PNAS, 1999, submitted).
  • Bioavailability is in fact influenced by various factors and, in the first place, by the chemical and physical characteristics of the compound.
  • the size of the molecule, its charge, its ability to bind to or mix with endogenous compounds such as biliary salts, plasma proteins or plasma or lymphatic lipids, its stability in the acid pH of the gastric juices are, for example, among the factors which may greatly influence the bioavailability of a compound.
  • a certain degree of solibility in an aqueous medium favours both their rapid dissolving in the biological fluids and their subsequent contact with the cell membranes, through which they then diffuse as a result of active or passive transportation processes; water-solubility alone, however, does not per se ensure optimal bioavailability.
  • a compound In order to achieve this object, a compound must also have certain degree of lipo-solubility to enable it to have an efficient interaction with the cell plasma membranes which constitute barriers to be crossed by passive diffusion.
  • lip-solubility since, in the tissues, there is a system of “solvents” formed by lipids of the cell membranes and by the interstitial and cytoplasmic liquids, absorption represents an extremely complex process which is dependent on the chemical and physical characteristics of the compound; although, on the one hand, lip-solubility favours the passage of the compound through the cell membranes, on the other hand, this passage is controlled and is dependent proportionally on the concentration of the compound in the aqueous phase, which is also partly correlated with its ability to ionize in a physiological medium.
  • novel covalent derivatives of alkanolamides of monocarboxylic and dicarboxylic acids with aminoalcohols can usefully be used as drugs with lipid/water partition coefficients and/or with solubility levels which are clearly favourable to interaction with biological membranes.
  • the hydrogen of the alcoholic residue of the alkanolamine is substituted by specific groups which can give a covalent bond with the oxygen.
  • novel drugs have been found to be functionally active, as such, on the CB2 cannabinoid receptor, whereas they are inactive on the CB1 receptor.
  • a clear synergy of action between the said compounds and molecules of an N-acylvanillin amide character which are functionally active on the CB1 receptor has also been shown.
  • a further subject of the present invention is the use of the above-mentioned novel covalent compounds—alone or in association with N-acylvanillin amide molecules active on the peripheral CB1 receptor—for the preparation of pharmaceutical compositions for human and veterinary use, which are effective for the treatment of the following pathological conditions: immuno-inflammatory conditions of various tissue regions, neurodegenerative conditions, conditions due to the spread of opportunistic viruses, as well as pathological conditions in which a non-psychomimetic effect of cannabinoids is noted; and their compositions for administration by various routes, including the parental, endovenous, intramuscular and subcutaneous routes, the gastroenteric route, the topical skin and muscous-membrane routes, and transdermal, ophthalmic and naso-pulmonary routes.
  • the present invention relates to compounds of the general formula (I): their enantiomers, diastereoisomers, racemates and mixtures thereof, in which:
  • a linear or branched alkyl radical saturated or with from 1 to 6 double bonds, a monocylic or polycyclic alkyl or alkenyl radical, or an aryl, arylalkyl or heterocyclic radical having one or more heteroatoms, the radicals optionally being substituted with one or more groups selected from hydroxy, acylamide, keto, nitro, alkoxy, halogen, mercapto, alkylthio, alkyldithio or aryldithio, —N + R7R8R9 Z ⁇ , in which R7, R8 and R9 are identical to one another or different and may be alkyl, alkenyl or arylalkyl radicals and Z ⁇ is the anion of a pharmaceutically acceptable organic or inorganic acid;
  • R4 is a linear or branched alkylene radical saturated or with from 1 to 6 double bonds, a cycloalkylene or cycloalkylene radical, or an aryl, arylalkyl or heterocyclic diradical with one or more heteroatoms, the radicals optionally being substituted with one or more groups selected from hydroxy, acylamide, keto, nitro, alkoxy, halogen, mercapto, alkylthio, alkyldithio, or aryldithio, R5 and R6 have the meanings given below for R2 and R3, respectively, or R5 is a group of formula —Y—OH, where Y has the meaning described below in point (c);
  • R4 has the meanings described above and R10 is hydrogen or a linear or branched alkyl radical or an arylalkyl radical, in which, when R10 is hydrogen, the resulting carboxylic group may optionally be salified with an organic or inorganic base to form a pharmaceutically acceptable salt;
  • R2 is selected from hydrogen or an alkyl, alkenyl or arylalkyl radical
  • R3 is a group of formula (IV): in which:
  • Y is a linear or branched alkyl radical, optionally substituted with one or more phenyl groups, possibly substituted with one or more hydroxy and/or alkoxy groups;
  • X is selected from:
  • R11 is selected from: a linear or branched alkyl or alkenyl radical, possibly containing for 1 to 5 heteroatoms, which may be identical to one another or different, a monocyclic or polycyclic alkyl radical, an arylalkyl radical, an aryl radical or a heterocyclic radical which is aromatic or completely or partially saturated, having one or more heteroatoms, the radicals optionally being substituted with one or more groups selected from hydroxy, amino, acylamino, keto, ureide, guanidino, nitro, alkoxy, halogen, —O—PO 3 H 2 , —O—PO 2 H 2 , —O— SO 3 H, —SO 3 H, mercapto, alkylthio, alkyldithio, aryldithio, azido, —NHR9, —NR7R8, —N + R7R8R9 Z ⁇ , in which Z ⁇ is
  • R12 is selected from: a linear or branched alkyl or alkenyl radical possibly containing from 1 to 5 heteroatoms which may be identical to one another or different, a monocylic or polycyclic alkyl radical, an arylalkyl radical, an aryl radical or a heterocyclic radical which is aromatic, or completely or partially saturated, having one or more heteroatoms, the radicals optionally being substituted with one or more groups selected from hydroxy, amino, acylamino, keto, ureide, guanidino, nitro, alkoxy, —O—C 4 H 4 —W, halogen, —O—PO 3 H 2 , —O—PO 2 H 2 , —O—SO 3 H, —SO 3 H, mercapto, alkylthio, alkyldithio, aryldithio, azido, —NHR9, —NR7R8, —N + R7R8R9 Z ⁇ , in which Z
  • R13 has, independently, the meanings of R12, or may be hydrogen
  • R14 is selected from: a linear or branched alkylene or arylalkylene radical, possibly substituted with a hydroxy group or —O—CO—R15, in which R15 is an alkyl, alkenyl or arylalkyl radical, R7, R8 and R9 are as defined above, or R7 and R8 may form, together with the nitrogen atom to which they are bound, a ring of from 3 to 7 members as defined above, and Z ⁇ is a pharmaceutically acceptable inorganic or organic anion;
  • R2 and R5 are both present on the same molecule, they are preferably identical to one another.
  • R3 and R6 are both present on the same molecule, they are preferably identical to one another.
  • R1 is an alkyl radical, it is preferably saturated or mono-unsaturated. It preferably has from 1 to 23 carbon atoms, more preferably from 11 to 17 carbon atoms and even more preferably from 13 to 15 carbon atoms.
  • R4 is an alkylene radical, it is preferably saturated or mono-unsaturated. It preferably has from 1 to 20 carbon atoms, even more preferably from 6 to 14 carbon atoms.
  • R7, R8 or R9 is an alkyl or alkenyl radical, it preferably has from 1 to 7 carbon atoms. Even more preferably R7, R8 and R9 are identical to one another and are methyl groups.
  • R10 is an alkyl radical, it preferably has from 1 to 20 carbon atoms.
  • R10 is hydrogen and the resulting carboxyl group is salified, it is preferably a lithium, sodium potassium, calcium, magnesium, zinc, copper, ammonium, or mono-, di- tri- o tetra-alkyl ammonium salt.
  • preferred bases for the salification are mono-ethanolamine, N-(2-hydroxyethyl)dimethyl ammonium, choline or amino-acids amongst which lysine is preferred.
  • R2 is an alkyl or alkenyl group, it preferably has from 1 to 7 carbon atoms.
  • Y is an alkylene radical, it preferably has from 2 to 20 carbon atoms, even more preferably from 2 to 6 carbon atoms.
  • X is a cycloalkyl-ether or a thio-ether, it preferably has a ring with 5 or 6 members, even more preferably, it is selected from tetrahydropyran-2-yl, tetrahydrofuran-2-yl, tetrahydrothiopyran-2-yl, tetrahydrothiofuran-2-yl, 4-methoxytetrahydropyran-2-yl, or 1,4-dioxan-2-yl.
  • R11 or R12 is an alkyl or alkenyl radical, it preferably has from 1 to 25 carbon atoms.
  • R11 or R12 is an alkyl or alkenyl radical containing from 1 to 5 heteroatoms
  • these heteroatoms are preferably selected from sulphur, oxygen and nitrogen.
  • the ring When R7 and R8 form, together with the nitrogen atoms to which they are bound, a ring, the ring preferably has from 5 to 7 members.
  • the ring contains a further nitrogen atom and this nitrogen atom is substituted by an alkyl radical, it is preferably a methyl or an ethyl group.
  • this amine is preferably selected from piperidine, pyrrolidine, morpholine, piperazine and hydroxyethylpiperazine.
  • R14 is an alkylene radical, it preferably has from 1 to 10 carbon atoms, more preferably from 2 to 4 carbon atoms.
  • R15 is an alkyl or alkenyl radical, it preferably has from 1 to 7 carbon atoms.
  • Z ⁇ to preferably selected from chloride, bromide, sulphate, methane sulphonate, hydrogen phosphate, benzene sulphonate, p-toluene sulphonate, acetate, succinate and benzoate.
  • M + is preferably selected from the following cations: lithium, sodium, potassium, calcium, magnesium, zinc, copper, ammonium, mono-, di-, tri- or tetra-alkyl ammonium, more preferably monoethanol ammonium, N-(2-hydroxyethyl) dimethyl ammonium, or cations of choline or of an amino-acid, preferably lysine.
  • acylamino preferably means an acetylamino group.
  • alkoxy preferably means a methoxy group.
  • halogen preferably means chloro, bromo, iodo or fluoro.
  • pharmaceutically acceptable acid preferably means an acid selected from hydrochloric, sulphuric, phosphoric, methane sulphonic, benzene sulphonic, p-toluene sulphonic, acetic, succinic and benzoic acid.
  • pharmaceutically acceptable base preferably means a base which can form a lithium, sodium, potassium, calcium, magnesium, zinc, copper, ammonium, or mono-, di-, tri- or tetra-alkyl ammonium salt.
  • the base is preferably monoethanolamine, N-(2)-hydroxyethyl)dimethyl amine, choline or an amino-acid most preferably lysine.
  • arylalkyl radical preferably means a C 7 -C 10 arylalkyl radical, more preferably a benzyl group.
  • aryl radical preferably means a C 6 -C 10 aryl radical, more preferably a phenyl group.
  • heterocyclic radical preferably means the radical of a saturated, unsaturated or aromatic heterocycle with a ring having 5 or 6 members, more preferably selected from tetrahydrofuran, tetrahydropyran, dioxane, pyrrolidine, piperidine, morpholine, thiomorpholine, piperazine, N-methylpiperazine, pyrrole, thiophene, furan, pyrazole, imidazole, thiazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, quinoline, isoquinoline, indole, benzoimidazole, benzothiazole.
  • cycloalkyl radical or “cycloalkenyl radical” preferably means a ring with from 3 to 10 carbon atoms, more preferably 5 to 6 carbon atoms,
  • the compounds of the invention may be prepared by reaction an intermediate of formula (Ia): R1-CO-(R2)-Y-OH (Ia) in which R, R2 and Y are as defined above, with a compound of formula X′, where X′ is selected from: in which n is 0 or a whole number between 1 and 4,;
  • reaction for the condensation of the intermediates of formula (Ia) with the compounds X′ is generally carried out in an inert solvent and preferably at a temperature of between ⁇ 10° C. and the boiling point of the solvent used.
  • An organic base such as, for example, a tertiary amine, or an inorganic base such as a carbonate or a bicarbonate of an alkali-metal or alkaline-earth metal may also advantageously be used.
  • this carbonyl group may be activated for condensation in known manner, for example, by transforming it into a hydroxysuccinimide ester or into a mixed anhydride, or by carrying out the condensation reaction in the presence of a condensing agent such as a carbodiimide.
  • the compounds X′ are known and/or commercially available or may be prepared from known and/or commercially available products in accordance with methods well known to an expert in the art.
  • the compounds of formula (Ia) can be prepared as described in EP 0 550 008, EP 0 550 006 and EP 0 570 714 which are incorporated herein by reference.
  • the residue was crystallized from 30 ml of tert-butylmethyl ether.
  • the crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether and finally dried in a high degree of vacuum.
  • the yield of the reaction was 92%.
  • the residue was crystallized twice, first from 20 ml of ethyl acetate and then from 20 ml of tert-butylmethyl ether.
  • the crystallizate was separated by filtration, washed twice with 5 ml of cold tert-butylmethyl ether, and finally dried in a high degree of vacuum.
  • the yield of the reaction was 88%.
  • N-[2-benzylaminocarbonyl)oxyethyl]hexadecanamide had the following chemical and physical characteristics:
  • N-(2-hydroxyethyl) hexadecanamide 10 mmoles
  • THF tetrahydrofuran
  • 1.11 g of N-methylmorpholine (11 mmoles) was added and the mixture was further supplemented with 1.88 g of (2-bromoethyl) chloroformate (10 mmoles) slowly, dropwise, over a period of 30 minutes.
  • the resulting mixture was kept at ambient temperature with stirring for a further 3 hours and then evaporated to dryness. The residue was taken up with 20 ml of water and extracted 3 times with 20 ml of ethyl acetate.
  • the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness.
  • the residue was taken up with 50 ml of anhydrous tetrahydrofuran and supplemented with 1.70 g of piperidine (20 mmoles).
  • the mixture was heated to reflux with stirring for 6 hours; it was then cooled to ambient temperature and supplemented with 20 ml of water and 60 ml of ethyl acetate.
  • the aqueous phase was discarded the organic phase was washed with 10 ml of cold 2M NH 3 solution and then with 20 ml of cold water.
  • the aqueous phases were discarded and the organic phase was evaporated to dryness.
  • the residue was crystallized from 30 ml of ethyl acetate, cold.
  • the crystallizate was separated by filtration, washed twice with 5 ml of cold ethyl acetate and finally dried under a high degree of vacuum.
  • the yield of the reaction was 89%.
  • N-(2-hydroxyethyl) oleoylamide (10 mmoles) was dissolved in 75 ml of tetrahydrofuran (THF) with stirring.
  • THF tetrahydrofuran
  • the solution was cooled to 4° C. and supplemented with 1.11 g of N-methyl morpholine (11 mmoles) and 1.19 g of ethyl chloroformate (11 mmoles).
  • the resulting mixture was kept at 4° C. for 30 minutes with continuous stirring and then for a further 24 hours at ambient temperature. The mixture was then evaporated to dryness under vacuum.
  • the residue was taken up with 50 ml of water and extracted 3 times with 30 ml of ethyl acetate; the organic phases were washed twice with 20 ml of water, recombined and evaporated to dryness.
  • the residue was purified by preparative chromatography on silica gel with the use of a mixture of ethyl acetate and hexane in a ratio of 50:50, as the eluent. The fractions containing the product were recombined and evaporated to dryness.
  • the oily residue was dried under a high degree of vacuum (yield 80%).
  • a useful parameter for evaluating the properties of a compound in relation to its possible absorption is in fact constituted by the coefficient of partition between the lipid phase and the aqueous phase, which is considered to be an expression of its lipophilicity and its degree of hydrophilicity.
  • the partition parameter RM between the lipid and the aqueous phase, extrapolated from thin-film partition chromatography was calculated; this parameter is commonly used to evaluate the lipophilic characteristics of compounds (Tomlinson E. J. Chromatogr. 1975, 113, 1) and is commonly used, for example, for local anaesthetics, in which a correlation has been shown between this parameter and biological activity (Bachrata M. et al. J. Chromatogr. 1979, 171, 29-36).
  • the results obtained were as follows:
  • Water-solubility may, however, also be achieved by introducing substituents which can be ionized and which can thus be salified; compounds with good solubility in aqueous solvents are thus produced, this characteristic being particularly important both for ensuring absorption and for the administration of the pharmacological agent in aqueous solution, for example, by a parenteral route.
  • the compounds of the invention were tested with the use of biochemical tests in vitro which are described in the following biological examples.
  • the compounds are identified on the basis of the number of the example given in the preceding chemical examples section above.
  • Rat RBL-2H3+ leukemic basophilic cells, which selectively express the cannabinoid CB2 receptor, and mouse N18TG2 neuroblastoma cells which selectively express the CB1 cannabinoid receptor were used.
  • the cells were cultivated as described above (Facci L. et al. (1995) Proc. Natl: Acad: Sci. U.S.A. 92:: 3376-3380; Bisogno T. et al. 1997 J. Biol. Chem., 272: 3315-3323).
  • WIN 55,212.2 was used as the selectively agonist synthetic ligand for the CB2 receptor.
  • SR141716A was used as the selective antagonist for the CB1 receptor.
  • HU-210 was used as the selective antagonist for the CB2 receptor.
  • [ 3 H]SR141716A (55 Ci/mmol) was supplied by Amersham; [ 3 H]WIN55,212-2 (43 Ci/mmol) was supplied by NEN.
  • the binding tests were performed with membranes of the cells resuspended in 50 mMol Tris pH 7.0 buffer; 2.5 mMol MgCl 2 , 0.8 mMol EDTA; 0.05% bovine serum albumin (BSA); 0.01% ethanol, in the presence of 100 ⁇ M of phenyl-methyl-sulphonyl fluoride (PMSF-Sigma), with the use, of 300 pM of [ 3 H]SR141716A and of [ 3 H]WIN55,212-2, respectively, as the ligand.
  • PMSF-Sigma phenyl-methyl-sulphonyl fluoride
  • the membranes were incubated for 90′ at 30° C. and filtered on glass microfibre filters (GFC-Whatman) and the radioactivity was detected by liquid scintillation.
  • the specific binding was calculated with the use of either 10 ⁇ M SR141716A or 10 ⁇ M HU-210.
  • the Ki values were calculated by Chang-Prusoff's equation and expressed as concentration ⁇ M.
  • the tests were performed with the aim of checking whether the binding of the molecules of the present invention to the CB2 receptor has functional significance.
  • the dosages of cAMP were performed on RBL-2H3+ cells flowing together in Petri dishes with six wells (Falcon); the cells were stimulated for 10′ at 37° C. with 1 ⁇ M of forskolin (Fluka) in 400 ⁇ l of medium without serum, containing 20 mM HEPES, 0.1 mg/ml BSA and 0.1 mM 1-methyl-3-isobutyl xanthine (Sigma) and either ethanol or alkanolamide molecules with or without the addition of HU-210. After incubation, the cells were extracted and the levels of cAMP were evaluated with a suitable Amersham kit in accordance with the producer's method. The data were expressed in IC50 ⁇ M.
  • the covalent derivatives of the invention can thus usefully be used for the treatment of inflammatory processes, and also those with hyperalgic components—both with a neurogenic basis and with an immunogenic basis—associated with immuno-inflammatory pathological conditions, and also autoimmune conditions, with neurodegenerative conditions associated with excitotoxic processes, as well as for conditions in which a non-psychomimetic effect of cannabinoids is known, all effects being attributable to an activity mediated by the CB2 receptor; amongst these, the following pathological conditions are mentioned by way of non-limiting example: neurological conditions such as, for example, multiple sclerosis, peripheral neuropathies—both somatic and autonomic—with various aetiologies, anoxic-ischaemic strokes and thromboses, cranial and spinal trauma, neurodegenerative conditions (AIDS—complex
  • the derivatives of the present invention may be administered by a parenteral systemic route (endovenously, intramuscularly, subcutaneously), a rectal route, or an oral route but also by a topical route (dermal and mucosal, ophthalmic, naso-pulmonary) and by a transdermal route.
  • the dosages in which they are used may vary according to the administration route and to the seriousness of the disease and of the general condition of the patient. In any case, the expected therapeutic dosages are from 0.1 mg/die to 1 g/die for a period of between one week and three months of continued administration. According to the chronic nature of the condition, the treatment may be repeated in various cycles.
  • the derivatives according to the invention may be administered in pharmaceutical compositions with excipients or diluents which are acceptable from the point of view of pharmaceutical use and are suitable for the purposes and in any case are such as to permit and/or to optimize adsorption by the selected administration route.
  • formulations in solution or suspension and also those produced with the use of preliminary micronization techniques and/or co-micronization with other active ingredients or with excipients for parental administration are envisaged; for the ophthalmic route, liquid forms as eye lotions and solid or semisolid forms as inserts, gels and ointments may be selected, and for oral administration they may be in the form of capsules, tablets, powders and pellets and also in gastroresistant formulations and may also be produced with the use of preliminary microencapsulation, liposomization and micellization techniques.
  • topical routes including the transdermal route, formulations as suppositories, micro-enemas, creams, ointments, sprays, gels, foams, dressings of various thicknesses and patches may be used. All of the possible pharmaceutical forms indicated for the various administration routes may also be formulated with excipients or technological processes suitable for producing fast-release or slow-release medicaments which the derivatives of the invention.
  • the compounds of the present invention may also be used effectively as cosmetic ingredients having the function of conditions and/or rheological additives.
  • a further subject of the present invention is therefore the use of the compounds of formula (I) in cosmetics.
  • Each lyophilized ampoule contains: Compound of Example 6 30 mg (co-micronized with mannitol) N-(4-hydroxy-3-methoxybenzyl)oleoyl amide 30 mg (co-micronized with mannitol) mannitol 80 mg each solvent ampoule contains: soya lecithin 40 mg water for injectables to make up to 2 ml

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US20130303528A1 (en) * 2006-10-16 2013-11-14 The Board Of Trustees Of The University Of Arkansas CB2 Receptor Modulators in Neurodegenerative Diseases and Applications of the Same
ITMI20122127A1 (it) * 2012-12-13 2014-06-14 Epitech Group Srl Derivati polietilenglicolici di palmitoiletanolammide e aciletanolammidi analoghe

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WO2003061699A1 (en) * 2001-12-27 2003-07-31 Japan Tobacco, Inc. Remedies for allergic diseases
WO2003075917A1 (en) 2002-03-08 2003-09-18 Signal Pharmaceuticals, Inc. Combination therapy for treating, preventing or managing proliferative disorders and cancers
US6825209B2 (en) 2002-04-15 2004-11-30 Research Triangle Institute Compounds having unique CB1 receptor binding selectivity and methods for their production and use
DK1374903T3 (da) * 2002-06-26 2007-07-30 Innovet Italia Srl Farmaceutisk sammensætning til forebyggelse af udvikling og progression af mykotiske hudoverfladesygdomme
EP1714644B1 (en) * 2005-04-19 2012-08-08 Innovet Italia S.r.l. Pharmaceutical compositions for the treatment of chronic ulcerations
CN102351728A (zh) * 2011-08-08 2012-02-15 厦门大学 一种油酰乙醇胺及其衍生物的合成方法

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ITMI20122127A1 (it) * 2012-12-13 2014-06-14 Epitech Group Srl Derivati polietilenglicolici di palmitoiletanolammide e aciletanolammidi analoghe
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